Obesity is a major public health concern: the prevalence of obesity in the US has increased dramatically, reaching rates greater than 30%. Although lifestyle and pharmacological therapies are successful in the short term, subsequent regain of lost weight is common. Surgical approaches such as gastric banding and Roux-en-Y gastric bypass (RYGB) achieve weight losses of greater than 20% or 25% of body weight maintained for up to 15 years. RYGB results in rapid restoration of insulin sensitivity prior to appreciable weight loss. The mechanisms underlying the success of RYGB are poorly understood. RYGB is a dual procedure involving creation of a small gastric pouch and bypass of the remaining stomach and upper intestines such that ingested calories are rapidly delivered to more distal intestinal sites. How each separately contributes to the beneficial effects of the surgery has not been experimentally assessed. The present proposal directly assesses the consequences of nutrient delivery to the small intestine and will identify the underlying mechanisms using rat and nonhuman primate experiments. The experiments under the first specific aim expand our current rat model of intestinal nutrient delivery in lean rats to a diet-induced obesity model focusing on the elucidation of central and peripheral mechanisms. Our preliminary data in lean rats demonstrate that small volumes of jejunal nutrient infusions produce persistent reductions in food intake well beyond their caloric content and support a role for gut peptides in mediating these changes. The proposed experiments will further characterize such feeding inhibition in obese rats and will directly assess the roles of specific gut peptides, alterations in taste preferences and neural homeostatic signaling systems in the suppressions of food intake. Additional experiments will compare the hormonal profiles produced by intestinal nutrient infusion to that following sleeve gastrectomy, another bariatric procedure with significant efficacy. Finally, we will assess the potential role of vagal afferent signaling in mediating the effects of intestinal infusions. The experiments under the second specific aim translate these findings to nonhuman primates using our established nonhuman primate model that has been successful in elucidating feedback controls on food intake and gastric emptying that have direct relevance to man. Here we propose to characterize the feeding inhibitory effects of small intestinal nutrient delivery in rhesus monkeys as well as in our unique obese Bonnet macaques to assess potential mechanisms of action and determine the efficacy of such nutrient delivery for producing long term changes in food intake and body weight. . PUBLIC HEALTH RELEVANCE: The relevance of the proposed work is to provide an understanding of the mechanisms underlying the reductions in eating and body weight following gastric bypass surgery. This understanding could lead to less invasive but effective obesity therapies.